WO1980001379A1 - 1a-hydroxycalcioic acid and esters thereof - Google Patents
1a-hydroxycalcioic acid and esters thereof Download PDFInfo
- Publication number
- WO1980001379A1 WO1980001379A1 PCT/US1979/001083 US7901083W WO8001379A1 WO 1980001379 A1 WO1980001379 A1 WO 1980001379A1 US 7901083 W US7901083 W US 7901083W WO 8001379 A1 WO8001379 A1 WO 8001379A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vitamin
- acid
- methanol
- esters
- compound
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
Definitions
- This invention relates to compounds which are characterized by vitamin D-like activity.
- this invention relates to derivatives of vitamin D 3 .
- the antirachitic activity of the D vitamins, and especially vitamin D 3 , and their application as nutritional supplements is well known. It is also now well known that to be effective these vitamins must be metabolized in vivo to express the physiological functions with which they are associated.
- the vitamin is first hydroxylated in the liver to form 25-hydroxyvitamin D, considered to be the major circulating metabolite in the blood stream. This compound may then be further hydroxylated in the kidney, primarily producing 1 ⁇ ,25-dihydroxyvitamin D or 24,25-dihydroxyvitamin D.
- the 1 ⁇ -hydroxylated form of vitamin D is generally considered to be the physiologically active or hormonal form of the vitamin, and to be responsible for what are termed vitamin D-like activities, such as increasing intestinal absorption of calcium and phosphate, mobilizing bone mineral, and retaining calcium in the kidneys. The possibility remains, however, that further metabolism of 1 ⁇ , 25-dihydroxyvitamin D is required to elicite any or all of these responses.
- vitamin D A derivative of vitamin D has now been found which displays some antirachitic activity and which, it is believed, may be the metabolically active form of the vitamin responsible for some of the biological responses mentioned above.
- This compound has been identified as 1 ⁇ , 3 ⁇ -dihydroxy-9, 10-seco-24 -norchola-5, 7, 10(19)-trien-23-oic acid, more conveniently referred to herein as 1 ⁇ -hydroxycalcioic acid or
- the lyophyllized livers were twice extracted for 24 hours at 4° C with 1:1 chloroform:methanol, followed by filtration.
- the resultant residue was rinsed with 800 ml methanol, residual solvent being pressed out on the filter.
- the extracts were combined and evaporated on a rotary evaporator.
- the residue from the evaporation was partitioned in a system containing 100 ml H 2 O:200 ml methanol:200 ml chloroform.
- the aqueous layer was rendered alkaline (pH 8. 5) with ammonium hydroxide before partitioning.
- the aqueous phase was washed by the addition of 25 ml chloroform and r.epartioned.
- the initial chloroform phase was washed with 90 ml of water (pH 8.5) and 140 ml of methanol.
- the chloroform phases from the partitionings were combined and found to contain 2. 1% of the dosed tritium whereas the combined aqueous phases contained 6. 0% of the dosed tritium.
- the aqueous phases were evaporated to dryness on a rotary evaporator using ethanol to azeotrope residual water.
- the residue was filtered in 150 ml of 95% ethanol to remove precipitated proteins.
- the charged peak from DEAE was dissolved in 10 ml methanol and chromatographed on a 2 x 57 cm LH-20 Sephadex (a hydroxypropyl ether derivative of polydextran marketed by Pharmacia Corporation, Piscataway, N.J. ) column equilibrated and eluted with methanol.
- the peak fractions eluting between 110 and 170 ml were combined, representing a 65% recovery of radioactivity. This sample was evaporated to dryness and then dissolved in 7 ml methanol.
- Diazomethane (generated by standard methods and recovered in an ether solution) was added to the dissolved sample at room temperature to the retention of a yellow color, indicating an excess of the methyla iting agent.
- the solvents were evaporated under a stream of nitrogen and the residue was partitioned in 20 ml H 2 O (pH 85):40 ml methanol: 40 ml chloroform. It was found that methyl ester if ication had proceeded in 99% yield as computed from chloroform- soluble radioactivity.
- the chloroform phase was evaporated and chromatographed on a 1 ⁇ 57 cm LH-20 Sephadex column equilibrated and eluted with 40% hexane in chloroform.
- the ultraviolet spectrum obtained on a Beckmann model 24 recording spectrophotometer (Beckman Instrument, Inc. , Fullerton, California), demonstrated an absorbance maximum at 265 nm and a spectral shape characteristic of the vitamin D triene.
- This compound has the following structure:
- the identity of the compound was established by the following criteria:
- the ultraviolet spectrum demonstrates an intact vitamin D cis-triene.
- the molecular ion at M/e 388 is consistent with this structure.
- the prominent peaks at M/e 370 and 352 represent losses of one or both A-ring hydroxyls. That the A-ring contains both hydroxyl functions and is unaltered from the l ⁇ ,25-dihydroxy vitamin D A-ring is confirmed by the fragements at M/e 152 and 134.
- the ions at M/e 287, 269, and 251 represent the loss of the side chain arid subsequent loss of one or both A-ring. hydroxyls respectively, demonstrating unaltered C and D rings and an intact
- the fragment at M/e 314 represents a McLafferty rearrangement with loss of C 3 H 6 O 2 , demonstrating that the methyl ester moiety is on the 23-carbon and not at the 21-carbon. Unreported peaks in the spectrum are consistent with this structure.
- the compound isolated is the methyl ester of the natural product. This ester group can be hydrolysed by the addition of 10% KOH in 90% methanol and warming at 50° C under nitrogen for 60 minutes. The free acid can be obtained by slowly lowering the pH to pH 6 with 1 N hydrochloric acid, evaporating the solvents and suspending the mixture in 95% ethanol.
- this compound can be readily obtained in crystalline form by crystallization from alcoholic solvents, e. g. methanol.
- methyl ester instead of converting the methyl ester to the acid (l ⁇ -hydroxycalcioic acid ), it can, if desired, be converted to other alkyl esters in which the methyl group is replaced by such groups as ethyl, propyl, butyl, or benzyl.
- treatment of the methyl ester with sodium ethoxide results in trans-ester if ication with the formation of the corresponding ethyl ester (ethyl-lor-hydroxycalcioate).
- the propyl, butyl and benzyl esters can be obtained by treating the methyl ester with the appropriate sodium alcoholate.
- these various esters can be prepared from the acid by treatment with the appropriate alcohol, (e. g. methanol, ethanol, propanol, butanol or benzyl alcohol) in the presence of a suitable condensing reagent, such as a carbodimiide (e. g. dicyclohexylcarbodiimide).
- a suitable condensing reagent such as a carbodimiide (e. g. dicyclohexylcarbodiimide).
- R is selected from the group consisting of hydrogen, a hydrocarbon chain having from 1 to about 4 carbon atoms and benzyl.
- the biological activity of the compound was ascertained as described in U. S. Pharmacopeia, 14th Revision (Mack Publishing Co. , Easton, Pa. (1955)).
- the 1 ⁇ - hydroxycalcioic acid was admin istered i. p. daily for six days at a daily dose of 12 ng. in a propylene glycol vehicle. Controls received only the propylene glycol.
- Table 1 expressed as units of antirachitic activity per ⁇ g of compound.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nutrition Science (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19792953443 DE2953443C2 (de) | 1978-12-29 | 1979-12-06 | 1ALPHA, 3beta-DIHYDROXY-9,10-seco-24-Norchola-5,7,10,(19)-trien-23-SAEURE UND ESTER DAVON. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US440 | 1978-12-29 | ||
US06/000,440 US4209634A (en) | 1978-12-29 | 1978-12-29 | 1α-Hydroxycalcioic acid and esters thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1980001379A1 true WO1980001379A1 (en) | 1980-07-10 |
Family
ID=21691549
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1979/001083 WO1980001379A1 (en) | 1978-12-29 | 1979-12-06 | 1a-hydroxycalcioic acid and esters thereof |
Country Status (9)
-
1978
- 1978-12-29 US US06/000,440 patent/US4209634A/en not_active Expired - Lifetime
-
1979
- 1979-12-06 DE DE19792953443 patent/DE2953443C2/de not_active Expired
- 1979-12-06 JP JP55500246A patent/JPS6310947B2/ja not_active Expired
- 1979-12-06 CH CH646580A patent/CH642046A5/de not_active IP Right Cessation
- 1979-12-06 WO PCT/US1979/001083 patent/WO1980001379A1/en unknown
- 1979-12-17 IL IL58976A patent/IL58976A/xx unknown
- 1979-12-28 FR FR7931928A patent/FR2445315B1/fr not_active Expired
- 1979-12-28 IE IE2520/79A patent/IE49347B1/en unknown
- 1979-12-28 GB GB7944539A patent/GB2043074B/en not_active Expired
Non-Patent Citations (1)
Title |
---|
DeLuca et al, Vitamin D: Biochemical., Chem. Clin, Aspects Relate Calcium Metabolism Proc. Work Shop Vitam. D, 3ru 1977 p 113-22 * |
Also Published As
Publication number | Publication date |
---|---|
US4209634A (en) | 1980-06-24 |
GB2043074B (en) | 1982-12-22 |
JPS55501100A (US20100056889A1-20100304-C00004.png) | 1980-12-11 |
FR2445315A1 (fr) | 1980-07-25 |
JPS6310947B2 (US20100056889A1-20100304-C00004.png) | 1988-03-10 |
GB2043074A (en) | 1980-10-01 |
IE49347B1 (en) | 1985-09-18 |
DE2953443C2 (de) | 1986-12-11 |
CH642046A5 (de) | 1984-03-30 |
IE792520L (en) | 1980-06-29 |
IL58976A0 (en) | 1980-03-31 |
IL58976A (en) | 1982-12-31 |
DE2953443T1 (US20100056889A1-20100304-C00004.png) | 1980-12-11 |
FR2445315B1 (fr) | 1986-04-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4292250A (en) | Vitamin D derivatives | |
Esvelt et al. | Isolation and characterization of 1. alpha.-hydroxy-23-carboxytetranorvitamin D: a major metabolite of 1, 25-dihydroxyvitamin D3 | |
Holick et al. | 1, 24, 25-Trihydroxyvitamin D3: a metabolite of vitamin D3 effective on intestine | |
EP0407461B1 (en) | Novel cyclopentano-vitamin d analogs | |
CA1233187A (en) | Method for preparing 1-hydroxyvitamin d compounds | |
WO1980000338A1 (en) | Process for preparing side chain fluorinated vitamin d compounds | |
US4248791A (en) | 25-Hydroxy-26,26,26,27,27,27-hexafluorocholecalciferol | |
KR900008120B1 (ko) | 비타민 d₃유도체의 제조방법 | |
GB2077736A (en) | Vitamin d derivatives | |
US4226788A (en) | 24,24-Difluoro-1α,25-dihydroxycholecalciferol | |
US4201881A (en) | 24,24-Difluoro-1α,25-dihydroxycholecalciferol | |
GB2153829A (en) | Hydroxyvitamin d2 isomers | |
EP0450743A1 (de) | 24-Oxa-Derivate in der Vitamin D-Reihe | |
US5250523A (en) | Side chain unsaturated 1α-hydroxyvitanim D homologs | |
US4495181A (en) | 1,25-Dihydroxy-24-oxo-vitamin D3 and 1,23,25-trihydroxy-24-oxo-vitamin D3 | |
JP2001503403A (ja) | ビタミンd類似体 | |
EP0245524B1 (en) | Vitamin d 3 derivative | |
GB2044770A (en) | 24,24 - difluoro- 25 - hydroxycholecalciferol | |
US4209634A (en) | 1α-Hydroxycalcioic acid and esters thereof | |
RU2320644C2 (ru) | Аналоги витамина d, композиции, содержащие указанные аналоги, и их применение | |
IE67953B1 (en) | Side Chain Unsaturated 1alpha-Hydroxyvitamin D Homologs | |
Holick et al. | Chemistry and biological activity of vitamin D, its metabolites and analogs | |
EP0073465B1 (de) | Cholecalciferolderivate | |
DE3243150A1 (de) | Trihydroxy-vitamin-d(pfeil abwaerts)3(pfeil abwaerts)-verbindungen | |
EP0250755A2 (en) | Fluorine derivatives of vitamin D3 and process for producing the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Designated state(s): CH DE JP |
|
RET | De translation (de og part 6b) |
Ref country code: DE Ref document number: 2953443 Date of ref document: 19801211 Format of ref document f/p: P |